Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses

Abstract

Over half a century ago, D. S. Falconer first reported a mouse with a reeling gate. Four decades later, the Reln gene was isolated and identified as the cause of the reeler phenotype. Initial studies found that loss of Reelin, a large, secreted glycoprotein encoded by the Reln gene, results in abnormal neuronal layering throughout several regions of the brain. In the years since, the known functions of Reelin signaling in the brain have expanded to include multiple postdevelopmental neuromodulatory roles, revealing an ever increasing body of evidence to suggest that Reelin signaling is a critical player in the modulation of synaptic function. In writing this review, we intend to highlight the most fundamental aspects of Reelin signaling and integrate how these various neuromodulatory effects shape and protect synapses.

Keywords: ApoE receptors; Reelin; amyloid-β (Aβ); apolipoprotein E (ApoE); neurodegeneration; neurodegenerative diseases; neurotransmitter receptor; protein-tyrosine kinase; receptor; synaptic function; tyrosine-protein kinase (tyrosine kinase).

FIGURE 1.

Reelin's role in stabilizing the cytoskeleton. Reelin signaling participates in axonal and dendritic outgrowth and maturation by stabilizing the cytoskeleton. A and B, microtubule stability is promoted by Reelin through VLDLR-dependent activation of Lis1 (reviewed in Refs. , , and 11) (A) and inhibition of GSK-3β (reviewed in Ref. 31) through activation of the Dab1/PI3K/Akt pathway, which also activates an mTOR-dependent process that promotes the outgrowth and stabilization of dendrites (reviewed in Refs. , , and 11) (B). C, Reelin promotes actin stability through the ApoER2/Dab1/PI3K pathway by inducing LIMK1-dependent inactivation of cofilin (reviewed in Ref. 3). D, this ApoER2/Dab1/PI3K pathway can also mediate the formation of axons by activating the RhoGTPase Cdc42 (8). E, independent of PI3K, Reelin stabilizes actin by triggering C3G activation of Rap1 through Crk family proteins (Crk), which is essential for normal neocortical lamination and postnatal hippocampal dendritogenesis (12, 13).

FIGURE 2.

Regulating Reelin signaling. A, the function of Reelin is regulated by proteolytic processing. The diagram depicts the domain structure of Reelin and the N- and C-terminal proteolytic cleavage sites (red and orange scissors, respectively). B, Reelin regulates BDNF signaling (hypothetical). Reelin increases the phosphorylation of CREB by enhancing Ca²⁺-influx through NMDARs (1) (29). CREB activation (phosphorylation) drives BDNF expression (2) (74). This BDNF can be released at the activated synapse and bind TrkB receptors (3), which promote actin stability through Cdc42 and Rac activity (4) (48). Both Reelin binding and TrkB/BDNF signaling can inhibit Reelin-mediated NMDAR phosphorylation by inducing the proteolytic processing of ApoER2 (5) (36, 47), whereby the ECD acts as a dominant negative receptor (6) (37) and the ICD can inhibit the transcription of Reelin (7) (38).

FIGURE 3.

Reelin's protective role against synaptic dysfunction. A and B, Reelin enhances the Ca²⁺ conductance of NMDARs (reviewed in Ref. 5) (A), leading to enhanced AMPAR insertion and LTP (B). C and D, Aβ can induce synaptic weakening (LTD) through agonizing mGluR5 and α7-nAChRs (C) (reviewed in Refs. and 57), which promote glutamate receptor (NMDAR and AMPAR) endocytosis (D). E, elevated Ca²⁺ concentrations can activate calpain and drive Cdk5-mediated tau hyperphosphorylation (reviewed in Ref. 62), which destabilizes microtubules. F, Reelin can inhibit tau phosphorylation by inhibiting GSK-3β (reviewed in Ref. 31). G, ApoE4 inhibits the Reelin signal by sequestering ApoER2 in the endosome (85, 87).

FIGURE 4.

ApoER2, ApoE, and APP all converge to regulate Aβ formation. A and B, the production of oligomeric Aβ depends on the proteolytic processing of APP, which is sequentially cleaved initially by a α- or β-secretase followed by γ-secretase cleavage. A, Non-amyloidogenic processing of APP. The α-secretases are present in the extracellular space and cleave APP within the Aβ region of the protein, preventing the release of Aβ upon γ-secretase cleavage. B, amyloidogenic processing of APP. β-Secretases are found mostly in the endosome and cleave APP to yield the Aβ peptide (reviewed in Ref. 50). C and D, APP and ApoER2 share multiple adaptor proteins that affect their localization and Aβ formation (C). C, the surface localization of APP and ApoER2 and non-amyloidogenic processing of APP are altered by the extracellular binding of F-spondin (left panel) (66) and intracellular interactions with Fe65 (middle panel) (72) and X11α/β (right panel) (67–70). ApoER2 binds the thrombospondin repeats 1–4 (pink triangles) of F-spondin, whereas APP binds the Reelin and Spondin domain of F-spondin (65, 66). The NPXY domain of APP (blue diamond) binds to the phosphotyrosine binding domains (PTB) of both Fe65 and X11α/β (69), whereas ApoER2 binds a second PTB domain of Fe65 (via the NPXY domain, white circle) (72) or the PDZ domains of X11α/β via the alternatively spliced proline-rich insert (purple oval) (68). D, the addition of ApoE4 induced an X11α/β-dependent co-endocytosis of APP and ApoER2, leading to increased amyloidogenic processing of APP (67).